The novel dopamine D4 receptor agonist (PD 168,077 maleate): doses with different effects on locomotor activity are without effect in classical conditioning

Conditioning is normally selective to the most likely predictors of motivationally significant events and some dopamine (DA) agonists produce dysfunction in this process. Moreover, the DA D(4) receptor is implicated in normal and abnormal functions that have some dopaminergic basis (e.g., in attention deficit hyperactivity disorder and schizophrenia). We therefore used locomotor activity to identify doses of a novel D(4) receptor agonist (PD 168,077) with contrasting behavioral effects (over the range 0.064-1 mg/kg). Doses that either did (0.064 mg/kg) or did not (0.5 mg/kg) significantly increase activity were then tested using aversive and appetitive procedures, in which conditioning was reflected in decreased and increased response rates, respectively. Associating a signal with food or foot shock is normally reduced in trace conditioning, when stimulus events are separated in time. Similarly, animals normally learn relatively little about background stimuli that do not well predict food delivery or the onset of shock. Both doses of PD 168,077 were without effect on conditioning, whether appetitive or aversive, and irrespective of how informative the predictive stimulus was. Thus, we find no evidence that the D(4) receptor has any likely effect on associative learning or its disorder. Furthermore, D(4)-mediated hyperactivity was dissociable from cognitive effects.     

PLGA nanoparticles for oral delivery of hydrophobic drugs: influence of organic solvent on nanoparticle formation and release behavior in vitro and in vivo using estradiol as a model drug

The aim of present investigation was to screen different solvents for optimizing nanoparticle preparation in terms of particle size, entrapment efficiency, and finally, release behavior using a model drug estradiol. Nanoparticles were prepared following emulsion-diffusion-evaporation method using didodecyldimethyl ammonium bromide (DMAB) or polyvinyl alcohol (PVA) as stabilizers. Ethyl acetate (EA), acetone (ACE), chloroform (CHL), and dichloromethane (DCM) were used as organic solvents either individually or in combinations. DMAB when used as surfactant led to smaller particle size as compared to PVA irrespective of the solvents and combinations used, but on the other hand, PVA produced particles with higher entrapment when combinations of solvents used. DCM in combination with EA resulted in highest entrapment with both the stabilizers. All the formulations exhibited similar in vitro release profile (Zero order) irrespective of stabilizer (DMAB or PVA) used, however, the average release per day was higher in case of DCM formulations due to greater entrapment. In situ uptake studies suggest that smaller the particle size better is the uptake. The bioavailability from nanoparticles was assessed in male Sprague Dawley (SD) rats at a dose of 1 mg drug/rat. EA/DMAB (size 116.0 +/- 2.6 nm) and DCM:EA 70:30/DMAB (size 253.0 +/- 5.5 nm) showed the release for 9 and 5 days, respectively, whereas EA/PVA (size 279.3 +/- 2.5 nm) released the drug over the periods of 3 days suggesting that particle size has significant role in determining the fate of nanoparticles in vivo. Histopathological examination revealed absence of any inflammatory response with the formulations under the studied period.     

Refusal of blood transfusion by Jehovah��s Witness women: a survey of current management in obstetric and gynaecological practice in the UK

Background

Refusal of blood transfusion by Jehovah’s Witness (JW) women poses potential problems for obstetrics worldwide as haemorrhage remains a major cause of maternal morbidity and mortality. There is a general consensus that morbidity and mortality rates in association with childbirth and gynaecological interventions are higher in these women than in the general population. We conducted a postal questionnaire survey of current practice among UK consultant obstetricians and gynaecologists to establish the practices that could contribute to poor outcomes in these women.

Materials and methods.

The main variables of interest were: use of a multi-disciplinary approach; the acceptable minimum haemoglobin (Hb) concentration before vaginal delivery and abdominal hysterectomy as low to medium risk scenarios and open myomectomy as a high risk scenario for haemorrhage; Hb concentration thresholds for iron supplementation; and the use of oral iron, intravenous iron, erythropoietin and cell salvage as potential management tools.

Results

The response rate was 28%. Sixty percent of gynaecologists and 85% of obstetricians reported having a protocol for the management of JW women. Forty-six percent of consultants adopt a multi-disciplinary approach which include anaesthetists and haematologists. A Hb concentration of >11–12g/dL is considered the minimum acceptable level by a majority (47%) prior to normal delivery and by 42% of gynaecologists prior to abdominal hysterectomy. For open myomectomy 28% of gynaecologists prefer a minimum level of 11–12 g/dL but a further 31% of gynaecologists prefer a minimum level of 12–13 g/dL.

Discussion.

A small but substantial proportion of consultants do not have protocols, operate on JW women with low Hb concentrations, do not use a lower Hb concentration threshold for supplementation, and do not adopt a multi-disciplinary approach, all of which could contribute to the reported poor outcomes in these women.     

Cortical silent period duration and its implications for surround inhibition of a hand muscle

Surround inhibition is a neural mechanism that assists in the focusing of excitatory drive to muscles responsible for a given movement (agonist muscles) by suppressing unwanted activity in muscles not relevant to the movement (surround muscles). The purpose of the study was to determine the contribution of γ‐aminobutyric acid_B receptor‐mediated intracortical inhibition, as assessed by the cortical silent period (CSP), to the generation of surround inhibition in the motor system. Eight healthy adults (five women and three men, 29.8 ± 9 years) performed isometric contractions with the abductor digiti minimi (ADM) muscle in separate conditions with and without an index finger flexion movement. The ADM motor evoked potential amplitude and CSP duration elicited by transcranial magnetic stimulation were compared between a control condition in which the ADM was activated independently and during conditions involving three phases (pre‐motor, phasic, and tonic) of the index finger flexion movement. The motor evoked potential amplitude of the ADM was greater during the control condition compared with the phasic condition. Thus, the presence of surround inhibition was confirmed in the present study. Most critically, the CSP duration of the ADM decreased during the phasic stage of finger flexion compared with the control condition, which indicated a reduction of this type of intracortical inhibition during the phasic condition. These findings indicate that γ‐aminobutyric acid_B receptor‐mediated intracortical inhibition, as measured by the duration of the CSP, does not contribute to the generation of surround inhibition in hand muscles.     

Appreciation of research information in patients with bipolar disorder

Objective:  Ethicists have debated whether patients with serious mental illness can appreciate the risks of research participation and make autonomous decisions. We compared the abilities of euthymic and manic bipolar patients to appreciate and make voluntary decisions regarding research participation.
Methods:  Twenty-six subjects with mania and 25 euthymic subjects reviewed hypothetical consent forms for three research studies of varying risk. We assessed subjects' appreciation of: their diagnosis and need for treatment; the researcher's role; the risks of participation; and the degree of influence of family, the treating clinician, and payment on decisions to participate.
Results:  Most subjects (92%) agreed they had bipolar disorder requiring medication treatment. Subjects were less likely to participate in riskier studies. About half of subjects erroneously believed that researchers would make decisions based solely on what would be the best care for them (therapeutic misconception); and in randomized medication trials, they mistakenly believed they had improved chances of receiving one treatment over another. There were no differences between mood groups on these measures. Over half of subjects (59%) indicated that their mental health provider might influence them to participate in a study even when they did not want to, but most rejected a role for family in decision making. Payment was rated as having little impact on decisions to participate in research.
Conclusion:  Mania does not substantially influence appreciation of research participation. Subjects with bipolar disorder, regardless of mood state, are at risk for therapeutic misconception and optimistic bias. Special protections may be needed when mental health professionals approach their own patients to participate in research.     

Abnormalities of tactile sensory function in children with dystonic and diplegic cerebral palsy

Recent studies have shown the presence of sensory dysfunction in adults with focal dystonias. The authors hypothesize that children with secondary dystonia due to cerebral palsy may share a similar sensory dysfunction. To test this hypothesis, they evaluated tactile spatial discrimination threshold using Johnson, Van Boven, Phillips domes in 10 children with cerebral palsy and upper extremity dystonia, 8 children with diplegic cerebral palsy without involvement of the arms, and 21 unaffected children. Both patient groups had poor tactile discrimination compared with controls. The authors therefore conclude that children with secondary dystonia and diplegia due to cerebral palsy have deficits of tactile sensation that are similar to deficits seen in adults with focal dystonia. These results are the first to test the spatial discrimination threshold using Johnson, Van Boven, Phillips domes in children with cerebral palsy.     

Chromoblastomycosis Associated with Bone and Central Nervous Involvement System in an Immunocompetent Child Caused by Exophiala Spinifera

Chromoblastomycosis is a chronic granulomatous infection of the skin and subcutaneous tissue caused by specific group of dematiaceous fungi. The infection results from traumatic injury and is seen more commonly on feet and lower legs. It is rarely seen in children and metastatic spread to other systems is exceptionally rare. We report a 12-year-old immunocompetent male child diagnosed with chromoblastomycosis on the lower leg, who in a span of few months developed osteomyelitis and left hemiparesis. Fungal culture showed growth of Exophiala spinifera. Child showed good improvement with voriconazole and itraconazole after 1 year of treatment. Skin lesions healed with minimal scarring and his power improved.     

Sociocultural and structural perpetuators of domestic violence in pregnancy: A qualitative look at what South Indian women believe needs to change

In India, reported rates of domestic violence rise as high as 31%. Abuse against pregnant women in India is associated with depressive and PTSD symptoms, and poor birth outcomes, yet no evidence-based interventions have been tested on this population. In this cross-sectional qualitative study, we sought perspective on South Indian women's concerns about abuse during pregnancy and what they believed would help. Participants cited economic dependence on husbands and sociocultural structures as factors perpetuating domestic violence. Women also described resilience factors that can protect against abuse. Our participants highlighted a requisite for interventions within health and social systems.